DESCRIPTION: (provided by the applicant) In this application, novel models are proposed to characterize 5-HT3 receptor regulation and trafficking of the serotonin transporter (SERT) in hippocampus and prefrontal cortex (PFC) and to determine how chronic nicotine use affects this regulation. SERT is primarily responsible for the termination of synaptic 5-HT activity by re-uptake and it is the therapeutic target for several disorders including depression. The hippocampus and PFC are brain regions critical in cognition learning and memory and nicotine has been shown to enhance these processes. 5-HT3 agonists enhance amphetamine stimulated release of serotonin (5-HT) in PFC but not in the hippocampus. The ability of 5-HT3 receptors to alter SERT trafficking will be modeled and studied in HEK-293 cells transfected with 5-HT3 receptors and SERT. Chronic nicotine treatment changes the responsiveness of the SERT to regulation by 5-HT3 receptors in hippocampus; after chronic nicotine treatment, 5-HT3 agonists are now able to enhance amphetamine stimulated 5-HT release. Models are proposed to determine how chronic nicotine use affects serotonergic systems. A superfusion system will be used to characterize 5-HT3 receptor-mediated regulation of 5-HT release via the SERT. Binding experiments and in situ hybridizations will be performed to determine how chronic nicotine affects 5-HT3 receptor and SERT expression.